Pregnancy provides a blueprint of highly synchronized maternal responses involving endocrine-immuneangiogenic mechanisms that are significantly influenced by gene-environment interactions. Although reproductive and neurocognitive anomalies have been reported in humans in response to environmental toxicants, experimental evidence in support of these observations is still elusive. Despite their discontinued industrial use, polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants and pose a health threat as they either mimic or block the actions of hormones. Since exposure to toxicants is mostly to mixtures, PCBs offer an ideal model system to delineate the unknown pathways and targets that underlie toxicant-induced reproductive health effects. PCBs affect either aryl hydrocarbon receptor (AhR) or estrogen receptor (ER) signaling pathways and may possess antagonistic or synergistic effects depending on the coplanar or non-co-planar structures. We hypothesize that in the context of in utero exposure, inflammation through Toll-like receptors (TLRs), angiogenesis, and fluid regulation are the key targets of PCBs at the maternal-fetal interface, and anomalies associated with these pathways become further manifested in response to genetic stress. Our recent results clearly provide support to this notion in that IL-10 deficiency in mice potentiates reproductive complications in response to Aroclor 1254. IL-10 is a potent anti-inflammatory cytokine and has been shown to be a critical factor for normal pregnancy outcome in humans. It is further hypothesized that in utero exposure to PCBs entails compromised pregnancy outcome and postnatal health. To understand the mechanistic underpinnings of PCB-induced in utero effects, we have recently established a mouse model and demonstrated that water channel Aquaporins and angiogenic functions are the novel targets of PCBs at the maternal-fetal interface. We propose to pursue the following specific aims to address our hypothesis and to extend our preliminary observations. Specific Aim 1: To determine the dosedependent effect of individual PCB congeners representing co-planar or non-co-planar structures on pregnancy outcome, amniotic fluid regulation, fetal development, spiral artery transformation, and local immune functions. Specific Aim 2: To delineate the role of novel pathways for PCB-induced effects, including aquaporins and angiogenesis. Specific Aim 3: To rescue PCB-induced pregnancy disruption by IL-10, estradiol, or human chorionic gonadotropin (hCG). Specific Aim 4: To evaluate the PCB-mediated inflammatory trigger through Toll-like receptors (TLRs). Evaluating the novel targets of PCBs in an experimental model with reproductive and neurocognitive health risks will lead us to understand novel mechanisms involved in gene-environment interactions and their health complications.